Small volume resuscitation with HyperHaes improves pericontusional perfusion and reduces lesion volume following controlled cortical impact injury in rats.
ABSTRACT The hyperosmolar and hyperoncotic properties of HyperHaes (HHES) might improve impaired posttraumatic cerebral perfusion. Possible beneficial effects on pericontusional perfusion, brain edema, and contusion volume were investigated in rats subjected to controlled cortical impact (CCI). Male Sprague-Dawley rats (n = 60) anesthetized with isoflurane were subjected to a left temporoparietal CCI. Thereafter, rats were randomized to receive HHES (10% hydroxyethylstarch, 7.5% NaCl) or physiological saline solution (4 mL/kg body weight) intravenously. Mean arterial blood pressure (MABP) and intracranial pressure (ICP) were determined before and following CCI, after drug administration and 24 h later. Regional pericontusional cortical perfusion was determined by scanning laser Doppler flowmetry before CCI, and 30 min, 4 and 24 h after injury. At 24 h brain swelling and water content were measured gravimetrically. At 7 days, cortical contusion volume was determined planimetrically. MABP was not influenced by HHES. ICP was significantly decreased immediately after HHES infusion (5.7 +/- 0.4 vs. 7.1 +/- 1.0 mm Hg; p < 0.05). Pericontusional cortical perfusion was significantly decreased by 44% compared to pre-injury levels (p < 0.05). HHES significantly improved cortical perfusion at 4 h after CCI, approaching baseline values (85 +/- 12%). While increased posttraumatic brain edema was not reduced by HHES at 24 h, cortical contusion volume was significantly decreased in the HHES-treated rats at 7 days after CCI (23.4 +/- 3.5 vs. 39.6 +/- 6.2 mm3; p < 0.05). Intravaneous administration of HHES within 15 min after CCI has a neuroprotective potential, as it significantly attenuated impaired pericontusional perfusion and markedly reduced the extent of induced structural damage.
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ABSTRACT: Previously, we reported that exogenous ubiquitin reduces cortical contusion volume and tends to reduce brain water content after controlled cortical impact injury Controlled Cortical Impact Injury (CCII) in rats. The mechanisms how exogenous ubiquitin exerts these effects remain unclear. Some studies revealed ubiquitin's immune modulatory abilities; therefore, we hypothesized that ubiquitin influences the local innate inflammatory response after CCII. Sprague-Dawley rats were exposed to CCII and randomized to either 1.5 mg/kg ubiquitin or 0.9% NaCl intravenously within 5 minutes after CCII. Immune cells were immunohistochemically stained with OX-42, myeloperoxidase (MPO), HIS48, ED1, and glial fibrillary acidic protein (GFAP). Apoptosis was analyzed by using terminal desoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL). Levels of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and IL-1 receptor antagonist (IL-1ra) were quantified using real-time reverse-transcriptase polymerase chain reaction (rt-PCR). ED1-positive cells were significantly increased in the pericontusional cortex after ubiquitin treatment at day 7 (823±182 cells/mm² vs. 550±246 cells/mm²; p=0.04). IL-10 expression after 3 days was significantly lower in the verum group (1.065¹⁰⁻⁵±0.6093¹⁰⁻⁵ vs. 2.266¹⁰⁻⁵±1.244¹⁰⁻⁵ relative messenger RNA expression; p=0.04) and TNF-α-levels tended to be higher in the verum group (22.01¹⁰⁻⁵±10.87¹⁰⁻⁵ vs. 9.34¹⁰⁻⁵±4.44¹⁰⁻⁵ relative messenger RNA; p=0.096). Quantification of apoptotic cells did not differ between the groups. Exogenous ubiquitin modulates the immune response by influencing the infiltration of macrophages or activated microglia and the expression of IL-10 and possibly TNF-α after CCII. The effects of these changes in immune response on posttraumatic neurodegeneration still need to be clarified.The Journal of trauma 12/2010; 70(5):1104-11. · 2.35 Impact Factor
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ABSTRACT: spinal cord injury (SCI) continues to be a problem without a definitive cure. Research based on improved understanding of the immunological aspects of SCI has revealed targets for treating and ameliorating the extent of secondary injury. Hypertonic saline (HTS), a substance both easy to create and to transport, has been investigated as an immunologically active material that can be used in a clinically relevant interval after injury. In this pilot study, HTS was investigated in a murine model for its abilities to ameliorate secondary injury after a severe spinal cord contusion. female C57Bl/6 mice with severe T8-10 contusion injuries were used as the model subjects. A group of 41 mice were studied in a blinded fashion. Mice received treatments with HTS (HTS, 7.5%) or normal saline solution (NSS, 0.9%) at 2 discreet time points (3 and 24 hours after injury.) A separate group of 9 untreated animals were also used as controls. Animals were assessed for autonomic outcome (bladder function). In a group of 33 mice, histological assessment (cellular infiltration) was also measured. bladder function was found to be improved significantly in those treated with HTS compared with those who received NSS and also at later treatment times (24 hours) than at earlier treatment times (3 hours). Decreased cellular infiltration in each group correlated with bladder recovery. the increased effectiveness of later administration time of the more osmotically active and immunomodulatory substance (HTS) suggests that interaction with events occurring around 24 hours after injury is critical. These events may be related to the invasion of leukocytes peaking at 8-24 hours postinjury and/or the peak benefit time of subject rehydration.Journal of neurosurgery. Spine 01/2011; 14(1):131-8. · 1.61 Impact Factor
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ABSTRACT: Increased systemic cytokines and elevated brain levels of monoamines, and hydroxyl radical productions are thought to aggravate the conditions of cerebral ischemia and neuronal damage during heat stroke. Dexamethasone (DXM) is a known immunosuppressive drug used in controlling inflammation, and hydroxyethyl starch (HES) is used as a volume-expanding drug in cerebral ischemia and/or cerebral injury. Acute treatment with a combined therapeutic approach has been repeatedly advocated in cerebral ischemia experiments. The aim of this study is to investigate whether the combined agent (HES and DXM) has beneficial efficacy to improve the survival time (ST) and heat stroke-induced cerebral ischemia and neuronal damage in experimental heat stroke. Urethane-anesthetized rats underwent instrumentation for the measurement of colonic temperature, mean arterial pressure (MAP), local striatal cerebral blood flow (CBF), heart rate, and neuronal damage score. The rats were exposed to an ambient temperature (43 degrees centigrade) to induce heat stroke. Concentrations of the ischemic and damage markers, dopamine, serotonin, and hydroxyl radical productions in corpus striatum, and the serum levels of interleukin-1 beta, tumor necrosis factor-alpha and malondialdehyde (MDA) were observed during heat stroke. After heat stroke, the rats displayed circulatory shock (arterial hypotension), decreased CBF, increased the serum levels of cytokines and MDA, increased cerebral striatal monoamines and hydroxyl radical productions release, and severe cerebral ischemia and neuronal damage compared with those of normothermic control rats. However, immediate treatment with the combined agent at the onset of heat stroke confers significant protection against heat stroke-induced circulatory shock, systemic inflammation; cerebral ischemia, cerebral monoamines and hydroxyl radical production overload, and improves neuronal damage and the ST in rats. Our results suggest that the combination of a colloid substance with a volume-expanding effect and an anti-inflammatory agent may provide a better resuscitation solution for victims with heat stroke.Experimental and Translational Stroke Medicine 10/2010; 2(1):19.